Birth Defects Insights: Sweet or Sour? Artificial Sweetener Safety during Pregnancy

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by John W. Kille, PhD, DABT

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It’s really no surprise why those little packets brightly colored and available at a diner near you have risen in popularity just as quickly as it takes to tear them open and dump in our coffees and iced teas. Most commonly used artificial sweeteners are high intensity sweeteners, which means that their sweetness intensity is many times greater than that of sugar (from 100 up to 20,000 times as sweet). But as a toxicologist with decades of experience evaluating data related to the safety of food additives during pregnancy, I can’t help but ask the question – Is our sweet obsession souring the health of fetal development? It’s an important question to answer as some consumer reports indicate the consumption of artificial sweeteners will continue to rise over the next ten years.

The Bottom Line:

Most pregnant women can safely ingest any artificial sweeteners approved by the international regulatory agencies and health authorities. The three main artificial sweeteners are: saccharin (e.g. Sweet’NLow), aspartame (e.g. NutraSweet and Equal), and sucralose (e.g. Splenda), although there are others, described below. These sugar substitutes are used in many different types of foods and drinks, but add little or no nutritional value.  Women who have phenylketonuria are a special exception to the safety of the artificial sweetener, aspartame, and may need to avoid it during their pregnancies.  Unrefined Stevia, a natural sweetener that is used as a sugar substitute, has not been approved for pregnancy, but its extract Rabaudioside-A, a purified glycoside of the Stevia plant, is considered safe for use during pregnancy under the FDA’s GRAS (Generally Recognized As Safe) classification for food additives.  These differences are explained in greater detail below. 

Currently, there are six high-intensity sweeteners that have been approved as safe food additives by the FDA.  These are (sweetness intensity X that of sugar): saccharin (100-700X), aspartame (200X), acesulfame potassium (Ace-K, 200X), sucralose (600X), neotame (7000-13,000X), and advantame (20,000X).  There are other sweeteners that are not high-intensity, but are non-nutritive. These are plant-derived and are considered safe by GRAS affirmation (see below).

But…(Yes, there is a “but”)…There are a Few Basic Facts and Cautions to Keep in Mind:

In general, a new food additive such as an artificial sweetener must go through rigorous testing in the laboratory and in animals, including pregnant animals, and clearly demonstrate safety before the FDA or any international regulatory body will allow its use in foods.  These, for the most part, have undergone very thorough testing prior to approval, and then toxicology specialists in the regulatory agencies critically analyze the data as it applies to human safety before they can be used in foods and beverages. The fact that most artificial sweeteners are high intensity sweeteners minimizes the amount that is necessary to provide the sweetness equivalent of a teaspoon of sugar. Therefore, your body is exposed to much less of the high intensity sweetener than it would be to sugar for the same level of sweetness. This also reduces the potential for adverse effects.  In addition, most are non-nutritive, which means that they provide no calories or so few calories that they are considered non-caloric.  This is the property that makes them attractive as adjuncts to a reduced-calorie diet.  The other side of that coin, however, is that “non-nutritive” means there is no nutritional benefit obtained by the mom-to-be or her baby when consuming these sweeteners.

One further point, non-nutritive sweeteners are widely divergent in their chemical structure, which means they are not likely to undergo the same chemical transformations in your body, or be metabolized the same way.  So, any claims you read of biological or chemical actions attributed to non-nutritive or high-intensity sweeteners as a class, other than eliciting the sensation of sweet taste, are likely to be inaccurate or at least an over-simplification of complex biochemical responses.  Just because one non-nutritive sweetener may be associated with a particular response, safety or otherwise, it is not correct to assume that all non-nutritive sweeteners do the same thing (as is often claimed, even by scientific researchers) unless they are individually tested under the same conditions and shown to produce the same results.

An excellent overview of high intensity sweeteners and their safety is available on the FDA website.

A Closer Look at the Three Main Artificial Sweeteners in Foods Today:

Saccharin

The oldest artificial sweetener is saccharin.  Saccharin has been consumed for a long time and has not been shown to cause birth defects.  It was discovered in 1879 and for a century or more, it was the only non-carbohydrate sweetener available to diabetics or diet-conscious consumers that could replace sugar until aspartame was approved in 1980.  This was followed somewhat later by other sweeteners such as sucralose, which was approved in 1998.  Since saccharin is not a sugar, diabetics can use it without a rise in blood glucose.  Because of this, and despite its metallic off-taste, its consumption and popularity steadily increased over the years, even to the extent that some preferred the taste over sugar (e.g. Tab cola with lemon). The discovery of saccharin preceded the organization of the FDA, so the rigorous safety testing that other high intensity sweeteners have undergone was not required for saccharin when it was introduced. Several safety studies have been conducted over the intervening years, most of which confirmed its safety.  However, in the late 1960s lifetime animal studies using a combination of saccharin and another sweetener, cyclamate, produced tumors in the bladders of rats.  Saccharin and cyclamate were placed on a U. S. list of likely human carcinogens, and FDA threatened to remove saccharin from foods.  But, due to the public outcry stemming from the potential removal of the only approved sugar substitute in the US at that time, Congress overruled the FDA (the only time this has occurred) and kept saccharin on the market.  Later scientific studies, however, showed that the bladder tumors occurred only in male rats and were due to a combination of events.  These included the production of a urinary protein that was the responsible cancer-instigating agent.  That protein, however, was only formed in male rats, not in humans.  Under certain conditions of urinary pH and testosterone the protein crystallized in the rat bladder causing irritation that ultimately led to the tumors. These studies, as well as epidemiologic studies in humans, showed that there was no human cancer risk, and saccharin was later removed from the list of possible cancer-causing agents by the National Institute of Environmental Health Sciences.  The National Cancer Institute reported that there is no scientific evidence that any of the artificial sweeteners approved for use in the United States cause cancer.  Nevertheless, while saccharin gained a scientific reprieve on its safety, cyclamate (the other sweetener in the rat bladder study) remains unapproved in the US as a potential carcinogen.  It is an approved sweetener in Canada, but then only if sold directly to the consumer, not as an ingredient in food products. Further, it must be identified as such on a label, and the label must also contain a statement indicating cyclamate should only be used in foods under the advice of a physician.

Aspartame

Aspartame is not a sugar.  It is a peptide composed of two amino acids (the building blocks of proteins), phenylalanine and aspartic acid, which together activate the sweetness receptors.  Because it is not a carbohydrate like sugar diabetics can consume it without raising their blood glucose levels.  It has an extensive safety database (approximately 200 studies) demonstrating its safety over a wide range of food uses and conditions. These studies, including investigations on fertility and embryo/fetal development, show no evidence that it causes birth defects except perhaps in pregnancies affected by an inherited maternal genetic defect (see below).  Although some members of the public and a few clinicians have raised concerns about its safety, most physicians and scientists, including FDA experts, as well as toxicologists in all international food regulatory review panels have determined that it is safe for use during pregnancy.

The one very important exception is in pregnant women who have a rare hereditary genetic disease called phenylketonuria, or PKU. These moms-to-be may need to avoid the phenylalanine contained in aspartame because they lack an enzyme that allows them to break down the phenylalanine into safe chemical components.  If they don't limit phenylalanine intake from all sources during pregnancy, excess phenylalanine can build up in their body, and in their fetus, and can cause brain damage and cognitive impairment in their baby even if the baby does not carry the defective PKU gene.  PKU occurs in approximately 1 out of 10,000 to 15,000 babies in the U.S. with higher rates of occurrence in whites and Native Americans than in blacks, Hispanics and Asians.  Fortunately, PKU is readily identified in babies as part of routine newborn screening.  When PKU is detected, a special medical diet designed by a neonatal nutritionist can prevent the negative effects of PKU if started early enough and followed throughout childhood and adolescence.  The clinical manifestations of PKU may be variable and some individuals with PKU are able to be less vigilant about their diet as they enter adulthood.  However, research has shown that a return to a strict limiting of phenylalanine intake is necessary during pregnancy to protect the developing fetus.  Fortunately, thanks to FDA-mandated labeling of products containing aspartame, avoiding phenylalanine is relatively easy for the few expectant moms with PKU. 

Sucralose

Sucralose is a non-nutritive sweetener that closely resembles table sugar (sucrose) in both taste and chemical structure. The difference from sugar is that it has been chemically transformed and contains three chlorine atoms substituted in very specific locations in the molecule.  These chlorine atoms do not come off and pose no adverse risk.  Their specific locations in the molecule are responsible for the 600-fold increase in sweetness over sugar.  But, more importantly, because of these changes in the molecule the body does not recognize sucralose as a sugar, so it is not able to digest and metabolize it as a source of calories.  Furthermore, because the body doesn’t recognize it as a sugar, diabetics can consume it safely without affecting their blood glucose, insulin or hemoglobin A1C.  Bacteria in the mouth likewise cannot metabolize sucralose, and that means that dental plaque bacteria cannot use it to produce the acid that causes tooth decay.  The body does not readily absorb it, and 85% is eliminated in the feces unchanged.  The small amount that is absorbed is processed safely by the body and eliminated in the urine.  It does not cross the placenta nor enter the fetus.  Sucralose has undergone an extensive series of safety studies (over 110), including those in pregnant animals to determine whether there are any potential adverse effects on sperm metabolism, fertility, embryo/fetal development including birth defects, or on any other aspect of the reproductive process.  These studies have shown no adverse effects on fertility, pregnancy, or the normal development of offspring.

In general, the vast majority of people have no problems consuming artificial sweeteners.  But there are reports of some who may be sensitive to one or another sweetener and may develop unexpected responses after consuming it (e.g. headache, GI distress).  If you do experience some disturbance after drinking a diet drink or eating food that contains one of these sweeteners there is no known increased risk to your baby, but for your own comfort you may want to try products that use a different sweetener.

Other types of sweetener substitutes

There are other types of sweetener substitutes that are usually not high intensity sweeteners.  These are plant-derived, for example, from sources such as the Stevia plant.  These generally have not undergone the same rigorous safety testing as is required for a new food additive such as the high intensity sweeteners because they have some history over many years of being used as a food without adverse consequences.  Nevertheless, in order to affirm safety for a quality product the manufacturer usually undertakes what is known as a GRAS (Generally Recognized As Safe) Notice to FDA supporting its safety as a food.  While GRAS evaluations are voluntary, in order to be acceptable to FDA these are quite detailed in their assessment of safety and must be compiled by scientists qualified by training and experience in evaluating safety data in order for the conclusions of safety to be considered valid. If submitted to the agency (this is not required), FDA may choose to review it and challenge the assessment.  If FDA does not challenge it, the assessment of safety is allowed to stand and is considered a tacit “approval,” but one that may be challenged at any time the Agency finds it necessary, e.g. due to new information.

Rabaudioside-A, for example, is a purified glycoside of the Stevia plant (Stevia rebaudiana Bertoni ) that produces non-nutritive sweetness and is an ingredient in several foods. This has undergone a GRAS review that has not been challenged by FDA and is, therefore, accepted as safe for the general public including pregnant moms. 

Note, however, that whole leaf Stevia and crude Stevia extracts are not approved by regulators as safe sweeteners because there are reports in the scientific literature of adverse health effects that raise concerns, including cardiovascular and reproductive effects that FDA considers serious enough to withhold approval and warn against their consumption.  One critical take-home message here is that just because something is natural, it does not necessarily mean that it is safe, or any safer, than a manufactured or processed product.  Many natural products have potent components that can produce undesirable health consequences.  Where your health and the health of your baby are concerned, a product must be established safe by qualified experts and not assumed to be safe just because it is “natural”.

Digesting the Facts

Based strictly on high quality scientific evidence, FDA and other international regulatory authorities have concluded that the approved high-intensity sweeteners are safe for the general population, including pregnant women and their babies, under the conditions of use as a food additive.  There is no evidence of birth defects or any other adverse pregnancy effect associated with these sweeteners.

But… (There’s that “but” again.)

One health consideration for pregnant women who use artificial sweeteners is that they may be missing out on more nutritious foods and beverages.  For example, if you drink a lot of diet soda, you may be getting the fluids that a healthy diet recommends; however, you won’t be getting the nutrients found in milk or juice, which are beneficial to you and your developing baby.  So, if you are pregnant, or you work with pregnant patients, be sure (to encourage them) to eat a balanced diet and drink a variety of healthy beverages.

About the Author

John W. Kille, PhD, is the founder and principal of the consulting firm J. W. Kille Associates, which provides services in toxicology, regulatory affairs, risk assessment, and other areas related to the safety evaluation and development of food additives, pharmaceuticals, and medical devices. He has over 35 years' experience conducting experiments and evaluating data related to the safety of food additives and pharmaceuticals, specializing in the area of effects on pregnancy and embryo/fetal development. He served as the principle reproductive toxicologist on the development of sucralose for McNeil Specialty Products.

Dr. Kille received his BA from Lafayette College, his MS from Villanova University in biology (embryology), and his PhD from the University of Virginia in developmental biology. He attained board certification in toxicology from the American Board of Toxicology in 1985. He is a Teratology Society member and is currently Past Chair of the Constitution and Bylaws Committee.

About the Teratology Society

Scientists interested or are already involved in research related to topics mentioned in this blog are encouraged to join the Teratology Society and the 58th Annual Meeting June 23 – 27, 2018, the premier source for cutting-edge research and authoritative information related to birth defects and developmentally-mediated disorders. Teratology Society members include those specializing in cell and molecular biology, developmental biology and toxicology, reproduction and endocrinology, epidemiology, nutritional biochemistry, and genetics, as well as the clinical disciplines of prenatal medicine, pediatrics, obstetrics, neonatology, medical genetics, and teratogen risk counseling. In addition, the Teratology Society publishes the scientific journal, Birth Defects Research.  Learn more at www.Teratology.org. Find the Teratology Society on LinkedIn, Facebook, and Twitter

References:

High intensity sweeteners

Saccharin – development of bladder tumors, relevance to humans 

What studies have shown about a possible association between specific artificial sweeteners and cancer

Cyclamate as a non-food product. Canadian Food Inspection Agency

Aspartame safety 

Incidence and treatment of PKU in the US  

Newborn screening for PKU  

Sucralose, no effects on reproduction

Sucralose, assessment of teratogenic potential (birth defects)

Stevia purified glycoside is regarded as safe by GRAS

Is Stevia whole leaf an FDA-approved sweetener?

 

 

 

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